First-in-human, phase I, dose-escalation study of selective PI3K{alpha} isoform inhibitor MLN1117 in patients (pts) with advanced solid malignancies.

2501 Background: PI3K signaling is aberrantly activated in many solid tumors; isoform-selective targeting may enable robust inhibition of this pathway in PIK3CA mutant tumors while sparing signaling in normal tissues. This study (NCT01449370) evaluated the safety, MTD, preliminary antitumor activity and pharmacokinetics/pharmacodynamics (PK/PD) of an investigational PI3Kα isoform-selective inhibitor, MLN1117. Methods: Pts age ≥ 18 with advanced solid tumors (except primary brain tumors) and known PIK3CA mutation status received oral MLN1117 once daily (QD, 100–300 mg) or 3 days per wk (MWF, 200–1200 mg, or MTuW, 200–900 mg) in 21-d cycles. Dose escalation proceeded via a 3+3 design based on cycle 1 (C1) DLTs. Plasma concentrations of MLN1117 for PK analyses were evaluated in C1. PI3K pathway biomarkers were assessed in skin biopsies via immunohistochemistry. Results: At data cut-off, 76 pts had enrolled; 24/29/23 pts to QD/MWF/MTuW schedules; median of 3 cycles per group. C1 DLTs occurred in: 2 QD pts (AL...